CH629257A5 - METHOD FOR PRODUCING SYMMETRIC CAROTINOIDS. - Google Patents

Description

The invention relates to a process for the production of symmetrical carotenoids from the phosphonium salts of the molecule halves by electrochemical oxidation.

Numerous synthetic routes are known for the production of carotenoids, in particular β-carotene. However, the known processes have a number of disadvantages, particularly as regards the yields or the accessibility of the starting materials. In addition, there are complex reaction conditions because the exclusion of water and oxygen or the maintenance of low temperatures are necessary.

German patent 1,068,709 describes a process for the preparation of β-carotene according to the synthesis principle C20 + C20 from axerophthylphosphonium salt and vitamin A aldehyde in a Wittig reaction in a solvent which is as anhydrous as possible and in a nitrogen stream with exclusion of oxygen from the air. One disadvantage of this process is that the chemically very sensitive and technically difficult to produce vitamin A aldehyde is used as the starting material.

HJ Bestman and O. Kratzer have described in the Chemischeberichte, Volume 96, pages 1899 ff. (1963) that phosphinalalkylenes, which are prepared from the phosphonium salts under the conditions of the Wittig reaction, by the action of oxygen with elimination of Tri -phenylphosphine oxide and formation of a double bond can dimerize. The use of this reaction for the production of β-carotene from triphenylphosphine axerophthylene is described in DT-PS 1 148 542 and only leads to carotene in a 35% crude yield. Also in a reference in Liebigs Annalen der Chemie, volume 721, pages 34 ff. (1969) it is confirmed that when using this dimerization with oxygen or air for the production of

ß-Carotene or carotenoids unsatisfactory yields can be achieved.

D. B. Denney in J. Org. Chem. 28, page 778 ff. (1963) describes that acylmethylenephosphoranes can be dimerized with peracetic acid with the elimination of triphenylphosphine oxide and the formation of a double bond. Denney was unable to dimerize phosphoranes which have no carbonyl group in the β-position to the phosphorus atom, such as triphenylbenzylidene phosphorane, with peracetic acid.

According to HJ Bestmann, L. Kisielowski and W. Distler (An -gew. Chem. 88, pp. 297 ff. (1976), the oxidation of alkylidenetriphenylphosphoranes using phosphite-ozone adducts in toluene or dichloromethane as a solvent can be carried out ß-Carotene can be obtained in this way in a 75% yield, but the reaction requires the maintenance of very low temperatures around -70 to -80 ° C.

A process has been found for the preparation of symmetrical carotenoids from phosphonium salts of the molecular halves of these symmetrical carotenoids, which is characterized in that phosphonium salts of the molecular halves are subjected to an electrochemical oxidation in a solvent in the presence of a base, the molecule halves with the elimination of substituted phosphine oxide dimerize.

Anodic coupling and condensation reactions are known, e.g. the coupling of two carboxylic acids known as Kolbe reaction, with elimination of carbon dioxide. The course of the Kolbe reaction is very dependent on the structure of the carboxylic acid residue. In particular, double bonds on the 2-carbon atom reduce the yield considerably (B.C.L. Weedon, "Kolbe Electrolytic Synthesis" in "Advances in Organic Chemistry", Volume 1, page 1 ff., Interscience Publishers Inc., New York 1960).

It was therefore surprising that the anodic condensation of the phosphonium salts leads to the corresponding dimers in good yields under conditions that are technically easy to implement.

The implementation can be shown schematically for the production of ß-carotene as follows:

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electrochemical oxidation / base

In this formula, R1, R2, R3 represent aromatic, aliphatic or cycloaliphatic radicals, for example phenyl, tolyl, cyclohexyl or butyl. X stands for the rest of an inorganic or organic strong acid, for example hydrogen sulfate, sulfate, phosphate, tetrafluoroborate, acetate, toluenesulfonate, benzenesulfonate. In addition, it is of course also possible to use phosphonium salts with acid residues other than anions which are inert under the reaction conditions. The preferred anion is hydrogen sulfate.

Phosphonium salts, which are used for the process according to the invention for the synthesis of symmetrical carotenoids, are compounds with tetrasubstituted phosphorus as a cation in which the substituent is the molecular half of the carotenoid and the remaining three substituents are the radicals R1, R2, R3. You can, for example, from the corresponding alcohols or esters according to methods described in the literature, for example according to DE-PS 1 068 709, DE-PS 1 158 505, DE-PS 1 155 126 or according to the information in Houben-Weyl, volume 12 / 1, pages 79 ff.,

Georg Thieme-Verlag, Stuttgart, 4th edition, 1963.

The preferred phosphonium salts are optionally substituted triarylphosphonium salts, especially the triphenylphosphonium salts, tricycloaliphatic phosphonium salts, especially tricyclohexylphosphonium salts, or trialkylphosphonium salts, especially tributylphosphonium salts.

Substituted phosphine oxide in the sense of this description is a phosphine oxide with the radicals R1, R2, R3 as a substituent.

The process according to the invention relates in particular to the production of carotenoids with 10 to 40 carbon atoms in the isoprenoid structure, preferably carotenoid compounds with 20 to 40 carbon atoms. The carotenoid compounds are characterized by a number of conjugated double bonds. As a rule, 3 to 11, preferably 7 to 11, double bonds are present. If necessary, two of these double bonds can be designed as triple bonds.

Symmetrical carotenoids in the context of this invention are, for example, hydrocarbons (carotenes) and their oxidized derivatives (xanthophylls), which are composed of 8 isoprenoid units in such a way that the arrangement of the isoprenoid units in the middle of the molecule runs in opposite directions, so that the two central methyl groups in relation to one another in 1 , 6-position and the remaining non-terminal methyl groups to the neighboring central methyl group are each in the 1,5-position. At the center of a carotenoid there is a chain of conjugated double bonds.

All carotenoids can be formally derived from the open chain

Derive structure of the lycopene (C40H56), namely by cyclization, by dehydrogenation, by hydrogenation or by oxidation or by combinations of these reactions.

Examples of phosphonium salts of half-molecules are: Axerophthylphosphonium hydrogen sulfate for the production of ß-carotene, 3,7, ll, 15-tetramethyl-hexadeca-2,4,6,8, 10,14-hexaenyl-l-triphenylphosphonium hydrogen sulfate for the production of Lycopene, 5- (2 ', 6', 6'-trimethyl-cyclohexen-r - yl-l ') - 3-methylpentadien-2,4-yl-l-triphenylphosphonium hydrogen sulfate for the production of l, 10- Bis- (2 ', 6', 6'-tri-methyl-cyclohexen-r-yl-r) -3,8-dimethyl-deca-l, 3,5,7,9 - pentaen, 3,7, ll, 15-tetramethyl-2,4,6,8,10-hexadeka-pentaen-30-l-yl-triphenyl-phosphonium hydrogen sulfate for the production of 1,2,1''2'-tetrahydrolycopene, 9- (2 ' , 6 ', 6'-Trimethyl-4' - methoxy-r-cyclohexen-r-yl) -3,7-dimethyl-2,4,6,8-nona-tetraen-l-yl-triphenylphosphonium hydrogen sulfate for the preparation von Zeaxanthindimethyläther, 9- [2 ', 3', 4'-Trime-35 thylphenyl-r] -3,7-dimethyl-2,4,6,8-nonatetraen-l-yl-triphe-nylphosphonium hydrogen sulfate for the production of Re-nierapurpurin.

The following may also be mentioned, for example: 9- [2 ', 6', 6'-trimethyl-4'-acetoxy-cyclohexen-l'-yl-r] -3.7-4o-dimethyl-2,4,6,8 -nonatetraen-l-yI-triphenyIphosphonium hydrogen sulfate for the production of zeaxanthin diacetate, which gives off zeaxanthin after cleavage of the acetyl groups, 9- [2 ', 6', 6'-trimethyl-3'-acetoxy-cyclohexen-r-yl -r] -3,7-dimethyl-2,4,6,8-nonatetraen-l-yl-triphenyl-phosphonium hy-45 drug sulfate for the preparation of isozeaxanthine diacetate, which gives off isoZeaxanthine after cleavage of the acetyl groups, 9- [2 ', 6', 6'-trimethyl-cyclohexen-r-on-3'-yl-r] -3,7-dimethyl-2,4,6,8-nonatetraen-1-yl triphenylphosphonium hydrogen sulfate for the production of canthaxanthin. 50 The preferred process conditions largely correspond to the conditions usual for anodic oxidations:

The usual materials are suitable as anode material, for example the platinum metals, graphite, gold, activated titanium, rhodium-plated titanium, platinum-coated titanium, platinum-coated tantalum, alloys of gold, e.g. with silver and with copper. A platinum metal is preferably used in the form of a sheet, mesh, expanded metal, rod or tube. Platinum is a particularly preferred anode material.

The usual materials are considered for the cathode, for example metals or graphite.

It is expedient to use a diaphragm to separate the cathode and anode compartments in order to ensure good material and current yields as well as trouble-free continuous operation at moderate cell voltages. The diaphragm can consist of a porous clay layer, a porous membrane or an ion exchange membrane.

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The amount of current passed is generally at least 2 F (corresponding to 2. 96494 A.s) per mole of phosphonium salt. It can normally be up to 6 times. Even a large excess does not disturb the course of the reaction.

The current density can be varied widely in this reaction and is approximately 1 to 500 A / dm2. A current density of 5 to 300 A / dm2 is preferably used. A current density of 100 A / dm2 is particularly preferred.

The upper temperature limit for the oxidation process is usually around 60 ° C, the lower limit around -20 ° C. It is preferable to work at temperatures in the range from 0 to 30 ° C.

Any liquid which sufficiently dissolves the phosphonium salt, the base and optionally a conductive electrolyte and which is sufficiently stable even under the conditions of the anodic oxidation can be chosen as the solvent. Water or mixtures of water and monohydric or polyhydric lower alcohols, ethers, hydrocarbons or chlorinated hydrocarbons with a relatively high water content are suitable. Due to the solubility of the organic component in water, these mixtures can also be two-phase. Examples of organic solvent components are methanol, ethanol, propanol, iso-propanol, isobutanol, glycol, glycerin, dioxane, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, petroleum ether, hexane, heptane, cyclohexane; Methylene chloride, chloroform, carbon tetrachloride. Examples of two-phase solvent mixtures are in particular heptane / water, methylene chloride / water, chloroform / water. The preferred solvent is water.

Alkali metal carbonates, such as sodium carbonate, potassium carbonate, ammonium carbonate, ammonia, alkali and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, barium hydroxide, alkali metal alcoholates, such as sodium or potassium hydroxide, sodium or potassium ethylate are advantageously used as bases which serve as proton acceptors.

In general, an at least equivalent amount of base, based on the phosphonium salt, or an excess, which can be up to 50 times, is used. A larger excess of base generally does not interfere with the course of the reaction.

When using water or aqueous solvent mixtures, the preferred bases include sodium and potassium carbonate, which are added solidly or expediently in the form of aqueous solutions.

A conductive electrolyte, for example an alkali sulfate, phosphate or borate, can additionally be added to the solution to be electrolyzed.

The order of addition of phosphonium salt solution, base and optionally electrolyte can vary:

For example, the phosphonium salt solution can be initially introduced and subjected to the electrolysis, while the calculated amount of the base, distributed over the electrolysis time, is added. Conversely, however, the solution of the base can also be introduced and electrolyzed while the phosphonium salt solution is added dropwise. It is also possible to mix the phosphonium salt and base before starting the electrolysis. The solution of an electrolyte can also be introduced and electrolyzed, and phosphonium salt solution and base can be added during the electrolysis. The process can be carried out batchwise or continuously.

The dimerization reaction is usually complete after the electrolysis, a precipitate being formed from the generally poorly soluble symmetrical carotenoid and substituted phosphine oxide when working in water. For working up, the precipitate is generally filtered off with suction, separated from the phosphine oxide, for example by treatment with alcohol, and the remaining symmetrical carotenoid is recrystallized or reprecipitated in a suitable solvent. In some cases, recrystallization or reprecipitation of the carotenoid may even be unnecessary.

If necessary, isomerization to the desired all-trans form of the carotenoid can be carried out in a manner which is customary per se, if this is desired or necessary. In the case of ß-carotene, such isomerization can be achieved, for example, by heating a ß-carotene suspension in aliphatic hydrocarbons, e.g. in heptane, or in water.

The method according to the invention for the production of symmetrical carotenoids is technically extremely advantageous. It was by no means to be expected that the sensitive unsaturated starting compounds and end products would not undergo any side reactions under the conditions of the anodic oxidation, e.g. Hydroxylations, formation of ketones and carboxylic acids and polymerization.

The particular advantage of the process - in contrast to the conversion of phosphonium salts after the Wittig reaction - is that the process can be carried out in water or in water-containing solvent mixtures. The possibility that the phosphonium salts can be reacted in aqueous solution creates an extraordinarily advantageous possibility for removing by-products which have arisen in the preparation of the phosphonium salts or which were present in the starting product by the aqueous or the aqueous Alcoholic solution or suspension of the phosphonium salts before the electrochemical oxidation with a water-immiscible solvent, for example Heptane, extracted. Another advantage is that the carotenoid obtained is very pure and in fine crystalline form and in high yields, especially when working in water.

In the process according to the invention, the end mother liquors of vitamin A synthesis, which contain a high proportion of cis isomers and can otherwise only be worked up in part and through lengthy and costly processes to give all-trans vitamin A, as starting material for the axerophthylphosphonium salt can be used for the production of β-carotene.

The carotenoids obtained by the process according to the invention can be used as pharmaceuticals, as additives for animal feed and as colorants for food and cosmetics.

example 1

The electrolytic cell consists of a cylindrical, approx.

1 liter glass nozzle with a face grind edge and a face grind cover, which is provided with ground grommets for receiving power cables, cooling coil, thermometer, drip judge, exhaust pipe. In the middle of the cell there is a platinum mesh as cathode, which is separated from the rest of the cell by a porous hollow clay cylinder closed at the bottom as a diaphragm. Dilute potassium hydroxide solution serves as the catholyte. Serve as anodes

2 platinum nets, each 20 x 10 mm edge length.

A solution of 1.085 mol of potassium carbonate in 450 ml of water is added to the cell and electrolysed for 6.5 hours at 4 A, while a solution of 0.083 mol of axophthyltriphenylphosphonium hydrogen sulfate in 250 ml of water is added. The temperature is kept at 15 ° C. For complete separation of the ß-carotene, stirring is continued for an hour, and then approximately

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Let stand for 18 hours. Then the precipitate is filtered off with suction, washed with warm water, the phosphine oxide is separated off by treatment with methanol at from 50 to 60 ° C. and the remaining β-carotene is dissolved in methylene chloride and precipitated with methanol; Yield 46.1%, based on the phosphonium salt used.

Example 2

In the electrolysis cell described in Example 1, a solution of 0.083 mol of axerophthyl triphenylphosphonium hydrogen sulfate and 0.258 mol of potassium sulfate in 750 ml of water is electrolyzed under the conditions mentioned in Example 1. A solution of 0.723 mol of potassium carbonate in 150 ml of water is added during the electrolysis. The yield of β-carotene is 27.5%, based on the phosphonium salt used.

Example 3

In the electrolysis cell described in Example 1, a solution of 1.085 mol of potassium carbonate, 0.1 mol of boron trioxide in 450 ml of water is electrolyzed at 4 A and 7 ° C. for 6.5 hours. During this time, a solution of 0.045 mol of axerophthyltriphenylphosphonium hydrogen sulfate in 125 ml of water is added. After working up according to Example 1, ß-carotene is obtained in a yield of 58.2%, based on the phosphonium salt used.

Example 4

In the electrolysis cell described in Example 1, a solution of 0.5 mol of potassium sulfate in 500 ml of water is electrolyzed at 3A for 6 hours. During this time, a solution of 0.083 mol of axerophthyltriphenylphosphonium hydrogen sulfate in 250 ml of H2Ó and a solution of 0.52 mol of potassium hydroxide in 200 ml of H20 are added dropwise so that a pH of 10 is not exceeded over 5 hours. 5 After working up according to Example 1, β-carotene is obtained in a yield of 44.1%, based on the phosphonium salt used.

Example 5

io Pseudojonon is reacted with sodium acetylene in liquid ammonia and subsequent hydrogenation of the triple bond 3,7, ll-trimethyl-dodeca-l, 4,6,10-te-traen-3-ol according to DT-PS 1 115 238 produced. According to DT-PS 1 068 710, the phosphonium hydrogen sulfate is produced therefrom with triphenyl-15 phosphine and sulfuric acid. This phosphonium salt is reacted with β-formylcrotyl acetate according to DT-PS 1 068 710 to l-acetoxy-3,7, 11, 15-tetra-methyl-hexadeca-2,4,6,8,10,14-hexaene. According to DT-PS 1 068 709, this ester becomes crystalline 3,7,11,15-tetramethylhexa-deca-2,4,6,8,10,14-hexaen-yl-1-triphenylphosphonium-hydro with triphenylphosphine 20 and sulfuric acid -genogen sulfate produced. Melting point 150 to 155 ° C.

Analogously to Example 1, a solution of 1.085 mol of potassium carbonate, 0.1 mol of boron trioxide in 450 ml of water is electrolyzed at 10 ° C. 0.045 mol of 3,7,11,15-tetramethylhexadeca-2,4,6,8,10,15-hexaen-yl-1-triphenylphosphonium hydrogen sulfate, dissolved in 125 ml of water, corresponding to Example 1, are added dropwise. After one hour, the mixture is allowed to come to room temperature and stirred for 18 hours. Methylene chloride is added and the amount of lycopene is determined by UV spectrometry from the methylene chloride solution; the yield is 37%.

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Claims (7)

629257 1. A process for the preparation of symmetrical carotenoids from phosphonium salts of the molecular halves of these symmetrical carotenoids, characterized in that phosphonium salts of the molecule halves are subjected to electrochemical oxidation in a solvent in the presence of a base, the molecule halves dimerizing with the elimination of substituted phosphine oxide. 2. The method according to claim 1, characterized in that the symmetrical carotenoids to be produced are carotenes with a hydrocarbon structure or their oxidized derivatives, which are composed of 8 isoprenoid units so that the arrangement of the isoprenoid units in the middle of the molecule is opposite, so that the two central Methyl groups in the 1,6 position and the remaining non-terminal methyl groups to the neighboring central methyl group are each in the 1,5 position. 2nd PATENT CLAIMS 3. The method according to claim 1 or 2, characterized in that water is used as solvent. 4. The method according to any one of the preceding claims, characterized in that an alkali metal alkali carbonate is used as the base. 5. The method according to any one of the preceding claims, characterized in that one carries out the electrochemical oxidation at temperatures in the range from -20 to + 60 ° C. 6. The method according to any one of the preceding claims, characterized in that one carries out the electrochemical oxidation at a current density in the range of 1 to 500 A / dm2. 7. The method according to any one of the preceding claims, characterized in that platinum is used as the anode material in the electrochemical oxidation.